Initial results of solitary pancreas transplants performed without regard to donor/recipient HLA mismatching.
We hypothesized that solitary pancreas transplants could be performed successfully even in the presence of poor HLA matching if an aggressive approach were taken with regard to immunosuppressive protocol and the performance of allograft biopsy. Seven pancreas-after-kidney transplants and seven pancreas transplants alone were performed without consideration given to the degree of HLA mismatching (MM) using tacrolimus (FK506)/mycophenolate mofetil (MMF)/prednisone maintenance therapy. Mean (+/-SD) total HLA MM was 4.8+/-1.2. All patients were followed for at least 6 months. The first four cases were induced with ATGAM for 7 to 10 days. In the remaining 10 cases, an ultrasound-guided percutaneous needle biopsy was attempted on a protocol basis 10 days after completing induction with OKT3 for 7 (n=2) or 14 (n=8) days. Overall patient survival, graft survival, and incidence of acute rejection requiring treatment were 86, 79, and 50%, respectively. Two patients receiving ATGAM developed grade III-IV rejection at 3 weeks. Both patients receiving OKT3 for 7 days developed early grade III rejection. However, only three of eight patients receiving OKT3 for 14 days developed rejection requiring treatment. Protocol biopsy was successfully performed in six of seven patients and uncovered three cases of otherwise undetectable grade III-IV rejection. Although based on a small number of cases, our results suggest that solitary pancreas transplants with a poor HLA match can be performed with an acceptable rejection incidence and graft survival rate using an OKT3/FK506/MMF/prednisone regimen with protocol biopsy.


[When an encircling aortic arch anomaly hides behind respiratory and digestive symptoms in children].
Aortic arch anomalies are relatively frequent and account for 15 to 20 % of all congenital cardiovascular malformations. They can be discovered in case of symptoms of airway or esophageal compression such as dysphagia, chronic cough, stridor, wheezing and recurrent respiratory infections. We report the cases of two children with encircling aortic arch anomaly. The 3-year-old boy had complained of chronic respiratory symptoms such as laryngitis and asthma since the age of 4 months. The 20-month-old boy presented with inter-mittent stridor, dysphagia and frequent vomiting. In both patients, the cervico-thoracic CT-scan showed a right aortic arch with retro-esophageal left subclavian artery and Kommerell's diverticulum. Surgery was curative. The understanding of normal and abnormal embryologic development of the aortic arch, and the knowledge of the different types of vascular compression and their clinical signs are mandatory for the early diagnosis and adequate treatment of such malformations.


Targeted sequencing identifies genetic polymorphisms of flavin-containing monooxygenase genes contributing to susceptibility of nicotine dependence in European American and African American.
Smoking is a leading cause of preventable death. Early studies based on samples of twins have linked the lifetime smoking practices to genetic predisposition. The flavin-containing monooxygenase (FMO) protein family consists of a group of enzymes that metabolize drugs and xenobiotics. Both FMO1 and FMO3 were potentially susceptible genes for nicotine metabolism process. In this study, we investigated the potential of FMO genes to confer risk of nicotine dependence via deep targeted sequencing in 2,820 study subjects comprising 1,583 nicotine dependents and 1,237 controls from European American and African American. Specifically, we focused on the two genomic segments including FMO1,FMO3, and pseudo gene FMO6P, and aimed to investigate the potential association between FMO genes and nicotine dependence. Both common and low-frequency/rare variants were analyzed using different algorithms. The potential functional significance of SNPs with association signal was investigated with relevant bioinformatics tools. We identified different clusters of significant common variants in European (with most significant SNP rs6674596, p = .0004, OR = 0.67, MAF_EA = 0.14, FMO1) and African Americans (with the most significant SNP rs6608453, p = .001, OR = 0.64, MAF_AA = 0.1, FMO6P). No significant signals were identified through haplotype-based analyses. Gene network investigation indicated that both FMO1 and FMO3 have a strong relation with a variety of genes belonging to CYP gene families (with combined score greater than 0.9). Most of the significant variants identified were SNPs located within intron regions or with unknown functional significance, indicating a need for future work to understand the underlying functional significance of these signals. Our findings indicated significant association between FMO genes and nicotine dependence. Replications of our findings in other ethnic groups were needed in the future. Most of the significant variants identified were SNPs located within intronic regions or with unknown functional significance, indicating a need for future work to understand the underlying functional significance of these signals.


Patient persistency with pharmacotherapy in the management of glaucoma.
To evaluate persistency with monotherapy in the treatment of glaucoma in patients new to pharmacological management. This population-based, retrospective cohort study, using managed care administrative claims data, included patients who were 20 years of age and older and who initiated monotherapy with betaxolol, brimonidine, dorzolamide, latanoprost, or timolol between May 1999 and January 2001. Follow-up continued through January 31, 2001, and prescription refill records for all ocular hypotensive medications were extracted for the full 21-month study period. The primary outcome measures were discontinuation and change (switching/adding on) of the index ocular hypotensive medication. Rates of discontinuation and discontinuation/change were compared using Cox regression methods; survival curves were generated. In all, 14,539 patients were prescribed any ocular hypotensive drug during the study period, and 2850 patients met all inclusion criteria. Patients treated with betaxolol, brimonidine, dorzolamide, or timolol were significantly (p < 0.05) more likely to discontinue and to discontinue/change the index therapy than were those treated with latanoprost. Results were confirmed in analyses adjusted for age and sex. Patients initially treated with latanoprost monotherapy are more persistent than those who begin treatment with beta-blockers, brimonidine, or the carbonic anhydrase inhibitor dorzolamide. Greater persistency with an initial ocular hypotensive therapy may improve health outcomes and reduce long-term costs to patients and health plans by limiting the increased resource use associated with discontinuations or changes in therapy.


Cultivation-Free Typing of Bacteria Using Optical DNA Mapping.
A variety of pathogenic bacteria can infect humans, and rapid species identification is crucial for the correct treatment. However, the identification process can often be time-consuming and depend on the cultivation of the bacterial pathogen(s). Here, we present a stand-alone, enzyme-free, optical DNA mapping assay capable of species identification by matching the intensity profiles of large DNA molecules to a database of fully assembled bacterial genomes (>10 000). The assay includes a new data analysis strategy as well as a general DNA extraction protocol for both Gram-negative and Gram-positive bacteria. We demonstrate that the assay is capable of identifying bacteria directly from uncultured clinical urine samples, as well as in mixtures, with the potential to be discriminative even at the subspecies level. We foresee that the assay has applications both within research laboratories and in clinical settings, where the time-consuming step of cultivation can be minimized or even completely avoided.


Illuminating the Psychological Experience of Elderly Loneliness from a Societal Perspective: A Qualitative Study of Alienation between Older People and Society.
Loneliness is a common experience among older people that is associated with health risks and negative well-being. As a psychological phenomenon, it has typically been defined in Western research literature as the discrepancy between desired and actual interpersonal relations. In our qualitative study in Hong Kong, we offer insight into ageing and loneliness in an urban environment of the non-Western world and propose to reconceptualise loneliness by exploring older people's experience of alienation at the societal level as an important but often neglected dimension of their loneliness. Thirty-seven community-dwelling, Chinese adults aged 65 and above were interviewed in focus groups and their accounts analysed and interpreted using a phenomenological approach. Findings revealed that focus group participants perceived insufficient care for older people, a growing distance between themselves and society, and their disintegrating identity in society to be primary sources of societal alienation. In response, older people adopted a more passive lifestyle, attributed marginalisation and inequality to old age, and developed negative feelings including unease towards ageing, vulnerability and helplessness, and anger. The emergence of these key components and underlying themes of societal alienation illuminated neglected facets of the psychological phenomenon of loneliness and highlighted new implications for policy, practice, and research from a societal perspective to address older people's loneliness in urban settings.


[Surgical treatment of postop abdominal wall hernia].
Two methods of combined plasty of postoperative abdominal wall hernia (PAWH), based on biochemical conception of pathogenesis of the disease, were proposed. Application of the methods had allowed to close the defect of any size of anterior abdominal wall. For the 1996-2001 period 221 patients with large, huge and giant PAWH were operated. Local and general complications in 29 (13.1%) patients had occurred, one patient died. Result of treatment in term up to 6 years was studied, recurrency of the disease was not revealed.


[Irradiation of choroid melanoma: justifiable therapy or medical experiment].
An analysis of published results of irradiation of choroidal melanomas shows that only two reports contain justified statistics. All other statistics are based on insufficiently long follow-up periods, and do not cover all patients irradiated so that artifacts of selection occur which cannot be checked. Arguments are adduced which show that the authors of the two relevant reports mentioned rightly changed their previously positive attitude towards irradiation of these tumors. With the exception of three circumscribed categories of patients, irradiation of choroidal melanomas is still an unjustifiable medical experiment.


Health benefits and health claims of probiotics: bridging science and marketing.
Health claims for probiotics are evaluated by the Panel on Dietetic Products, Nutrition and Allergies of the European Food Safety Authority. Despite a substantial amount of basic and clinical research on the beneficial effects of probiotics, all of the evaluated claim applications thus far have received a negative opinion. With the restrictions on the use of clinical endpoints, validated biomarkers for gut health and immune health in relation to reduction in disease risk are needed. Clear-cut criteria for design as well as evaluation of future studies are needed. An open dialogue between basic and clinical scientists, regulatory authorities, food and nutrition industry, and consumers could bridge the gap between science and marketing of probiotics.


Patient stratification based on prednisolone-vincristine-asparaginase resistance profiles in children with acute lymphoblastic leukemia.
To confirm the prognostic value of a drug resistance profile combining prednisolone, vincristine, and l-asparaginase (PVA) cytotoxicity in an independent group of children with acute lymphoblastic leukemia (ALL) treated with a different protocol and analyzed at longer follow-up compared with our previous study of patients treated according to the Dutch Childhood Leukemia Study Group (DCLSG) ALL VII/VIII protocol. Drug resistance profiles were determined in 202 children (aged 1 to 18 years) with newly diagnosed ALL who were treated according to the German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL)-92 protocol. At a median follow-up of 6.2 years (range, 4.1 to 9.3 years), the 5-year disease-free survival probability (pDFS) rate +/- SE was 69% +/- 7.0%, 83% +/- 4.4%, and 84% +/- 6.8% for patients with resistant (PVA score 7 to 9), intermediate-sensitive (PVA score 5 to 6), and sensitive (SPVA score 3 to 4) profiles, respectively (sensitive and intermediate-sensitive v resistant, P </=.05). Resistant patients were at increased risk of an early event (nonresponse or relapse within 2.5 years of diagnosis) compared with sensitive and intermediate-sensitive patients (P =.03). The profile did not identify patients at higher risk of late relapse, which was also observed for DCLSG ALL-VII/VIII patients now analyzed at a median of 7.5 years of follow-up (range, 4.4 to 10.8 years). Despite being nondiscriminative for late relapses, the resistant profile was still the strongest prognostic factor for COALL-92 patients in a multivariate analysis including known risk factors (P =.07). Drug resistance profiles identify patients at higher risk of early treatment failures and may, therefore, be used to improve risk-group stratification of children with ALL.


Beneficial effects of fruit extracts on neuronal function and behavior in a rodent model of accelerated aging.
Exposing young rats to particles of high-energy and charge (HZE particles) enhances indices of oxidative stress and inflammation and disrupts the functioning of the dopaminergic system and behaviors mediated by this system in a manner similar to that seen in aged animals. Previous research has shown that diets supplemented with 2% blueberry or strawberry extracts have the ability to retard and even reverse age-related deficits in behavior and signal transduction in rats, perhaps due to their antioxidant and anti-inflammatory properties. This study evaluated the efficacy of these diets on irradiation-induced deficits in these parameters by maintaining rats on these diets or a control diet for 8 weeks prior to being exposed to whole-body irradiation with 1.5 Gy of 1 GeV/n high-energy (56)Fe particles. Irradiation impaired performance in the Morris water maze and measures of dopamine release 1 month following radiation; these deficits were protected by the antioxidant diets. The strawberry diet offered better protection against spatial deficits in the maze because strawberry-fed animals were better able to retain place information (a hippocampally mediated behavior) compared to controls. The blueberry diet, on the other hand, seemed to improve reversal learning, a behavior more dependent on intact striatal function. These data suggest that (56)Fe particle irradiation causes deficits in behavior and signaling in rats which were ameliorated by an antioxidant diet and that the polyphenols in these fruits might be acting in different brain regions.


Effect of timing and method of cleft palate repair on dental arches at the age of three years.
The purpose of this study was to compare the influence of two different ages at the time of palatal closure and two surgical methods on the size of the dental arches at the age of 3 years in children, with CP, UCLP, and BCLP. In 88 children the one-stage palatal closure had been performed at the age of 1.8 years and in 92 children at the age of 1.1 years. In both groups palatal surgery had been performed with a V to Y push back procedure (Veau-Wardill-Killner) or with the Cronin modification. Dimensions of the maxillary arch in both groups at age 3 were smaller than in noncleft children, but the timing of palatal closure did not affect arch dimensions in children with CP, UCLP, or BCLP. Arch dimensions at 3 years of age were not related to the method used in palatal closure.


Spectrally multiplexed chromatic confocal multipoint sensing.
We present a concept for chromatic confocal distance sensing that employs two levels of spectral multiplexing for the parallelized evaluation of multiple lateral measurement points; at the first level, the chromatic confocal principle is used to encode distance information within the spectral distribution of the sensor signal. For lateral multiplexing, the total spectral bandwidth of the sensor is split into bands. Each band is assigned to a different lateral measurement point by a segmented diffractive element. Based on this concept, we experimentally demonstrate a chromatic confocal three-point sensor that is suitable for harsh production environments, since it works with a single-point spectrometer and does not require scanning functionality. The experimental system has a working distance of more than 50 mm, a measurement range of 9 mm, and an axial resolution of 50 μm.


Attitudes among students and teachers on vertical integration between clinical medicine and basic science within a problem-based undergraduate medical curriculum.
Important elements in the curriculum at the Faculty of Health Sciences in Linköping are vertical integration, i.e. integration between the clinical and basic science sections of the curriculum, and horizontal integration between different subject areas. Integration throughout the whole curriculum is time-consuming for both teachers and students and hard work is required for planning, organization and execution. The aim was to assess the importance of vertical and horizontal integration in an undergraduate medical curriculum, according to opinions among students and teachers. In a questionnaire 102 faculty teachers and 106 students were asked about the importance of 14 different components of the undergraduate medical curriculum including vertical and horizontal integration. They were asked to assign between one and six points to each component (6 points = extremely important for the quality of the curriculum; 1 point = unimportant). Students as well as teachers appreciated highly both forms of integration. Students scored horizontal integration slightly but significantly higher than the teachers (median 6 vs 5 points; p=0.009, Mann-Whitney U-test), whereas teachers scored vertical integration higher than students (6 vs 5; p=0.019, Mann-Whitney U-test). Both students and teachers considered horizontal and vertical integration to be highly important components of the undergraduate medical programme. We believe both kinds of integration support problem-based learning and stimulate deep and lifelong learning and suggest that integration should always be considered deeply when a new curriculum is planned for undergraduate medical education.


Case report: Understanding the impact of persistent tissue-localization of SARS-CoV-2 on immune response activity via spatial transcriptomic analysis of two cancer patients with COVID-19 co-morbidity.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected half a billion people, including vulnerable populations such as cancer patients. While increasing evidence supports the persistence of SARS-CoV-2 months after a negative nasopharyngeal swab test, the effects on long-term immune memory and cancer treatment are unclear. In this report, we examined post-COVID-19 tissue-localized immune responses in a hepatocellular carcinoma (HCC) patient and a colorectal cancer (CRC) patient. Using spatial whole-transcriptomic analysis, we demonstrated spatial profiles consistent with a lymphocyte-associated SARS-CoV-2 response (based on two public COVID-19 gene sets) in the tumors and adjacent normal tissues, despite intra-tumor heterogeneity. The use of RNAscope and multiplex immunohistochemistry revealed that the spatial localization of B cells was significantly associated with lymphocyte-associated SARS-CoV-2 responses within the spatial transcriptomic (ST) niches showing the highest levels of virus. Furthermore, single-cell RNA sequencing data obtained from previous (CRC) or new (HCC) ex vivo stimulation experiments showed that patient-specific SARS-CoV-2 memory B cells were the main contributors to this positive association. Finally, we evaluated the spatial associations between SARS-CoV-2-induced immunological effects and immunotherapy-related anti-tumor immune responses. Immuno-predictive scores (IMPRES) revealed consistent positive spatial correlations between T cells/cytotoxic lymphocytes and the predicted immune checkpoint blockade (ICB) response, particularly in the HCC tissues. However, the positive spatial correlation between B cells and IMPRES score was restricted to the high-virus ST niche. In addition, tumor immune dysfunction and exclusion (TIDE) analysis revealed marked T cell dysfunction and inflammation, alongside low T cell exclusion and M2 tumor-associated macrophage infiltration. Our results provide in situ evidence of SARS-CoV-2-generated persistent immunological memory, which could not only provide tissue protection against reinfection but may also modulate the tumor microenvironment, favoring ICB responsiveness. As the number of cancer patients with COVID-19 comorbidity continues to rise, improved understanding of the long-term immune response induced by SARS-CoV-2 and its impact on cancer treatment is much needed.


Studies on vascular permeability in hypertension: action of anthocyanosides.
The initial phase of renal hypertension induced by ligature of the abdominal aorta was accompanied by a transient increase in vascular permeability. This permeability increase has not the same intensity in all parts of the organism: it is greater in the skin and in the aorta wall than in the brain vessels. Treatment of rats with a flavonoid-type drug (anthocyanosides of Vaccinium myrtillus) for 12 days before the induction of hypertension kept the blood-brain barrier permeability normal and limited the increase in vascular permeability in the skin and the aorta wall. As previously demonstrated, the collagens of the blood vessel walls play an important role in the control of vascular permeability. Interaction of these collagens with the drug may be partly responsible for the protection against the permeability-increasing action of hypertension observed in the treated animals.


Consumers' and providers' perceptions of utilizing a computer-assisted cognitive behavioral therapy for childhood anxiety.
Computer-assisted cognitive behavioral therapy (CCBT) programs for childhood anxiety are being developed, although research about factors that contribute to implementation of CCBT in community mental health centers (CMHC) is limited. The purpose of this mixed-methods study was to explore consumers' and providers' perceptions of utilizing a CCBT for childhood anxiety in CMHC in an effort to identify factors that may impact implementation of CCBT in CMHC. Focus groups and interviews occurred with 7 parents, 6 children, 3 therapists, 3 project coordinators and 3 administrators who had participated in CCBT for childhood anxiety. Surveys of treatment satisfaction and treatment barriers were administered to consumers. RESULTS suggest that both consumers and providers were highly receptive to participation in and implementation of CCBT in CMHC. Implementation themes included positive receptiveness, factors related to therapists, treatment components, applicability of treatment, treatment content, initial implementation challenges, resources, dedicated staff, support, outreach, opportunities with the CMHC, payment, and treatment availability. As studies continue to demonstrate the effectiveness of CCBT for childhood anxiety, research needs to continue to examine factors that contribute to the successful implementation of such treatments in CMHC.


The reovirus M1 gene determines the relative capacity of growth of reovirus in cultured bovine aortic endothelial cells.
Since blood-borne viruses often interact with endothelial cells before tissue invasion, the interaction between viruses and endothelial cells is likely to be important in viral pathogenicity. Two reovirus isolates (type 1 Lang and type 3 Dearing) differ in their capacity to grow in cultured bovine aortic endothelial cells. The mammalian reoviruses have 10 double-stranded RNA gene segments in their genome. By using 24 reassortant viruses, observed differences in the capacity of different strains to grow in cultured endothelial cells were mapped to the M1 gene (P = 0.00019), which encodes the viral core protein mu 2. No differences were detected in binding or proteolytic processing of viral outer capsid proteins of parental virions between the two reovirus isolates. Northern blot analysis showed a decreased production of viral mRNA in endothelial cells infected with type 3 Dearing reovirus, but not type 1 Lang. Thus, we have identified a viral gene (the M1 gene) responsible for determining the difference in growth capacity of the two reovirus isolates in cultured endothelial cells. Reovirus is an attractive model in which to study the interaction of viruses with endothelial cells at a molecular genetic level.


Genetic Diversity of Non-O157 Shiga Toxin-Producing Escherichia coli Recovered From Patients in Michigan and Connecticut.
Shiga toxin-producing Escherichia coli (STEC) are important foodborne pathogens and non-O157 serotypes have been gradually increasing in frequency. The non-O157 STEC population is diverse and is often characterized using serotyping and/or multilocus sequence typing (MLST). Although spacers within clustered regularly interspaced repeat (CRISPR) regions were shown to comprise horizontally acquired DNA elements, this region does not actively acquire spacers in STEC. Hence, it is useful for further characterizing non-O157 STEC and examining relationships between strains. Our study goal was to evaluate the genetic relatedness of 41 clinical non-O157 isolates identified in Michigan between 2001 and 2005 while comparing to 114 isolates from Connecticut during an overlapping time period. Whole genome sequencing (WGS) was performed, and sequences were extracted for serotyping, MLST and CRISPR analysis. Phylogenetic analysis of MLST and CRISPR data was performed using the Neighbor joining and unweighted pair group method with arithmetic mean (UPGMA) algorithms, respectively. In all, 29 serogroups were identified; eight were unique to Michigan and 13 to Connecticut. "Big-six" serogroup frequencies were similar by state (Michigan: 73.2%, Connecticut: 81.6%), though STEC O121 was not found in Michigan. The distribution of sequence types (STs) and CRISPR profiles was also similar across states. Interestingly, big-six serogroups such as O103 and O26, grouped into different STs located on distinct branches of the phylogeny, further confirming that serotyping alone is not adequate for evaluating strain relatedness. Comparatively, the CRISPR analysis identified 361 unique spacers that grouped into 80 different CRISPR profiles. CRISPR spacers 231 and 317 were isolated from 79.2% (n = 118) and 59.1% (n = 88) of strains, respectively, regardless of serogroup and ST. Spacer profiles clustered according to the MLST analysis, though some discrepancies were noted. Indeed, use of both MLST and CRISPR typing enhanced the discriminatory power when compared to the use of each tool separately. These data highlight the genetic diversity of clinical STEC from different locations and show that CRISPR profiling can be used alongside MLST to discriminate related strains. Use of targeted sequencing approaches are particularly helpful for sites without WGS capabilities and can help define which strains require additional characterization using more discriminatory methods.


Evaluation of Treatment Coverage and Enhanced Mass Drug Administration for Onchocerciasis and Lymphatic Filariasis in Five Local Government Areas Treating Twice Per Year in Edo State, Nigeria.
The western region of Edo state in southern Nigeria is highly endemic for onchocerciasis. Despite years of mass drug administration (MDA) with ivermectin (IVM), reports suggest persistently high prevalence of onchocerciasis, presumably because of poor coverage. In 2016, twice-per-year treatment with IVM (combined with albendazole for lymphatic filariasis in the first round where needed) began in five local government areas (LGAs) of Edo state. We undertook a multistage cluster survey within 3 months after each round of MDA to assess coverage. First-round coverage was poor: among 4,942 people of all ages interviewed from 145 clusters, coverage was 31.1% (95% confidence intervals [CI]: 24.1-38.0%). Most respondents were not offered medicines. To improve coverage in the second round, three LGAs were randomized to receive MDA through a "modified campaign" approach focused on improved supervision and monitoring. The other two LGAs continued with standard MDA as before. A similar survey was conducted after the second round, interviewing 3,362 people in 87 clusters across the five LGAs. Coverage was not statistically different from the first round (40.0% [95% CI: 31.0-49.0%]) and there was no significant difference between the groups (P = 0.7), although the standard MDA group showed improvement over round 1 (P < 0.01). The additional cost per treatment in the modified MDA was 1.6 times that of standard MDA. Compliance was excellent among those offered treatment. We concluded that poor mobilization, medicine distribution, and program penetration led to low coverage. These must be addressed to improve treatment coverage in Edo state.


Bacteriophage SPP1 Chu is an alkaline exonuclease in the SynExo family of viral two-component recombinases.
Many DNA viruses concatemerize their genomes as a prerequisite to packaging into capsids. Concatemerization arises from either replication or homologous recombination. Replication is already the target of many antiviral drugs, and viral recombinases are an attractive target for drug design, particularly for combination therapy with replication inhibitors, due to their important supporting role in viral growth. To dissect the molecular mechanisms of viral recombination, we and others previously identified a family of viral nucleases that comprise one component of a conserved, two-component viral recombination system. The nuclease component is related to the exonuclease of phage lambda and is common to viruses with linear double-stranded DNA genomes. To test the idea that these viruses have a common strategy for recombination and genome concatemerization, we isolated the previously uncharacterized 34.1 gene from Bacillus subtilis phage SPP1, expressed it in Escherichia coli, purified the protein, and determined its enzymatic properties. Like lambda exonuclease, Chu (the product of 34.1) forms an oligomer, is a processive alkaline exonuclease that digests linear double-stranded DNA in a Mg(2+)-dependent reaction, and shows a preference for 5'-phosphorylated DNA ends. A model for viral recombination, based on the phage lambda Red recombination system, is proposed.


Fate of Aegilops speltoides-derived, repetitive DNA sequences in diploid Aegilops species, wheat-Aegilops amphiploids and derived chromosome addition lines.
The present study reports the cloning and characterization of an Aegilops speltoides-derived subtelomeric repeat, designated as pSp1B16. Clone pSp1B16 has 98% sequence homology with the previously isolated Ae. speltoides repeat Spelt1. The distribution of pSp1B16 and another Ae. speltoides repeat, pGc1R1, was analyzed in diploid Aegilops species, tetra- and hexaploid wheats, wheat-Aegilops amphiploids and derived chromosome addition lines by fluorescence in situ hybridization (FISH). Clones pSp1B16 and pGc1R1 revealed FISH sites in Ae. speltoides, Ae. sharonensis and Triticum timopheevii, whereas additional pGc1R1 FISH sites were observed in Ae. longissima and Ae. caudata. The pSp1B16 and pGc1R1 FISH patterns of the Aegilops chromosomes in the wheat-Aegilops amphiploids and chromosome addition lines are similar to those present in the Aegilops parent accession. We did not observe any evidence of pSp1B16 and pGc1R1 sequence elimination, which is in contrast to previous studies using similar hybrids and repeats. The presented data suggest that the genomic changes in synthetic amphiploids observed in previous studies might be caused by homoeologous recombination, which was suppressed in the amphiploid analyzed in this study.


Treatment and Prognosis of Solid and Cystic Brain Metastases in Patients with Non-Small-Cell Lung Cancer.
Brain metastasis (BM) is an important factor shortening the lives of patients with lung cancer. Patients with cystic BM have seldom been reported. Here, we compared the efficacy and prognosis of different therapeutic schedules for solid BM and cystic BM in patients with non-small cell lung cancer (NSCLC). A retrospective study was conducted of 355 patients with pathologically confirmed stage IV NSCLC, all of whom had BM. We analyzed the clinical characteristics of these patients and the efficacy of targeted drugs and chemotherapy regimens. A total of 255 patients with solid BM (cohort 1) and 33 patients with cystic BM (cohort 2) had evaluable efficacy. We evaluated these 33 patients in cohort 2. The median progression-free survival (PFS) and overall survival (OS) were 8.4 months and 23.0 months, respectively. A significant difference was observed between targeted regimens and chemotherapy treatment in terms of the PFS (12.6 months vs 6.3 months, P = 0.001) and OS (47.9 months vs 17.0 months, P = 0.007). Multivariate analyses showed that treatment regimen (chemotherapy) was a poor prognostic factor for PFS (P < 0.05). Cystic BM may be more likely to occur in patients with NSCLC with genetic mutations. A difference in prognosis was observed between patients who underwent targeted treatment and chemotherapy. A significant difference in intracranial PFS was observed between cohorts (cohort 1 vs cohort 2: 15.4 months vs 9.9 months, P = 0.015), and this advantage was clear in patients who did not receive targeted therapies (11.7 months vs 6.5 months, P = 0.003). However, the OS in patients with targeted therapies in cohort 2 was significantly longer than that in cohort 1 (23.4 months vs 47.9 months, P = 0.013). Patients with NSCLC, particularly those who develop cystic BM, should be genetically tested as much as possible to find out more suitable drug therapies.


Comparative aspects of subplate zone studied with gene expression in sauropsids and mammals.
There is currently a debate about the evolutionary origin of the earliest generated cortical preplate neurons and their derivatives (subplate and marginal zone). We examined the subplate with murine markers including nuclear receptor related 1 (Nurr1), monooxygenase Dbh-like 1 (Moxd1), transmembrane protein 163 (Tmem163), and connective tissue growth factor (Ctgf) in developing and adult turtle, chick, opossum, mouse, and rat. Whereas some of these are expressed in dorsal pallium in all species studied (Nurr1, Ctgf, and Tmem163), we observed that the closely related mouse and rat differed in the expression patterns of several others (Dopa decarboxylase, Moxd1, and thyrotropin-releasing hormone). The expression of Ctgf, Moxd1, and Nurr1 in the oppossum suggests a more dispersed subplate population in this marsupial compared with mice and rats. In embryonic and adult chick brains, our selected subplate markers are primarily expressed in the hyperpallium and in the turtle in the main cell dense layer of the dorsal cortex. These observations suggest that some neurons that express these selected markers were present in the common ancestor of sauropsids and mammals.


Stereoselective total syntheses and reassignment of stereochemistry of the freshwater cyanobacterial hepatotoxins cylindrospermopsin and 7-epicylindrospermopsin.
A stereoselective total synthesis of the structure 1 proposed for the freshwater cyanobacterial heptatotoxin cylindrospermopsin has been accomplished in approximately 30 operations starting from commercially available 4-methoxypyridine. Utilizing methodology developed by Comins, the tetrasubstituted piperidine A-ring unit of the hepatotoxin was efficiently constructed. The two remaining stereocenters in the natural product were then set by a stereospecific intramolecular N-sulfinylurea Diels-Alder cyclization/Grignard ring opening/allylic sulfoxide [2,3]-sigmatropic rearrangement sequence previously developed in these laboratories, leading to key intermediate 29. The stereochemical assignment of alcohol 29, which contains all six of the stereogenic centers of the natural product, was confirmed by an X-ray crystal structure determination of a derivative. Installation of the D-ring uracil moiety was effected by using our new methodology developed for this purpose, and construction of the C-ring guanidine completed the total synthesis of racemic structure 1. However, the (1)H NMR data for this compound do not match that of cylindrospermopsin, but instead agree with the data reported for 7-epicylindrospermopsin, a minor toxic metabolite that co-occurs with cylindrospermopsin. Therefore, we propose a revision of the stereochemical assignments of these natural products such that cylindrospermopsin is now represented as structure 2 and 7-epicylindrospermopsin is 1. This reassignment was further confirmed by Mitsunobu inversion of the C-7 alcohol 51 to epimer 52, and conversion of this compound to tetracyclic diol 57, which has previously been transformed to cylindrospermopsin (2).


Dopaminergic stimulation of cAMP accumulation in cultured rat mesangial cells.
Dopamine (DA) alters renal hemodynamics, and DA receptors have been demonstrated in isolated glomeruli. To determine the glomerular cell type bearing DA receptors, we studied the effect of dopaminergic agonists and antagonists on adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in rat glomerular mesangial and epithelial cells in culture. DA caused a marked dose- and time-dependent increase in cAMP accumulation in mesangial but not epithelial cells. The stimulatory effect of DA was abolished by the DA antagonists haloperidol, trifluoperazine, and cis-thiothixene but not by beta- or alpha-adrenergic or histamine antagonists. Similar to the effects of DA, two dopamine type I receptor agonists, fenoldopam and SKF 38393, markedly stimulated cAMP accumulation in the mesangial cells. Moreover, the effects of DA were blocked by Sch 23390, a specific DA1 receptor antagonist, but not domperidone, a specific DA2 antagonist. These results show that DA regulates cAMP accumulation in mesangial cells via DA1-type receptors.


Parametrically Amplified Low-Power MEMS Capacitive Humidity Sensor.
We present the design, fabrication, and response of a polymer-based Laterally Amplified Chemo-Mechanical (LACM) humidity sensor based on mechanical leveraging and parametric amplification. The device consists of a sense cantilever asymmetrically patterned with a polymer and flanked by two stationary electrodes on the sides. When exposed to a humidity change, the polymer swells after absorbing the analyte and causes the central cantilever to bend laterally towards one side, causing a change in the measured capacitance. The device features an intrinsic gain due to parametric amplification resulting in an enhanced signal-to-noise ratio (SNR). Eleven-fold magnification in sensor response was observed via voltage biasing of the side electrodes without the use of conventional electronic amplifiers. The sensor showed a repeatable and recoverable capacitance change of 11% when exposed to a change in relative humidity from 25-85%. The dynamic characterization of the device also revealed a response time of ~1 s and demonstrated a competitive response with respect to a commercially available reference chip.


Coding variants in NOD-like receptors: An association study on risk and survival of colorectal cancer.
Nod-like receptors (NLRs) are important innate pattern recognition receptors and regulators of inflammation or play a role during development. We systematically analysed 41 non-synonymous single nucleotide polymorphisms (SNPs) in 21 NLR genes in a Czech discovery cohort of sporadic colorectal cancer (CRC) (1237 cases, 787 controls) for their association with CRC risk and survival. Five SNPs were found to be associated with CRC risk and eight with survival at 5% significance level. In a replication analysis using data of two large genome-wide association studies (GWASs) from Germany (DACHS: 1798 cases and 1810 controls) and Scotland (2210 cases and 9350 controls) the associations found in the Czech discovery set were not confirmed. However, expression analysis in human gut-related tissues and immune cells revealed that the NLRs associated with CRC risk or survival in the discovery set were expressed in primary human colon or rectum cells, CRC tissue and/or cell lines, providing preliminary evidence for a potential involvement of NLRs in general in CRC development and/or progression. Most interesting was the finding that the enigmatic development-related NLRP5 (also known as MATER) was not expressed in normal colon tissue but in colon cancer tissue and cell lines. Future studies may show whether regulatory variants instead of coding variants might affect the expression of NLRs and contribute to CRC risk and survival.


Proteomics Approach Highlights Early Changes in Human Fibroblasts-Pancreatic Ductal Adenocarcinoma Cells Crosstalk.
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality worldwide. Non-specific symptoms, lack of biomarkers in the early stages, and drug resistance due to the presence of a dense fibrous stroma all contribute to the poor outcome of this disease. The extracellular matrix secreted by activated fibroblasts contributes to the desmoplastic tumor microenvironment formation. Given the importance of fibroblast activation in PDAC pathology, it is critical to recognize the mechanisms involved in the transformation of normal fibroblasts in the early stages of tumorigenesis. To this aim, we first identified the proteins released from the pancreatic cancer cell line MIA-PaCa2 by proteomic analysis of their conditioned medium (CM). Second, normal fibroblasts were treated with MIA-PaCa2 CM for 24 h and 48 h and their proteostatic changes were detected by proteomics. Pathway analysis indicated that treated fibroblasts undergo changes compatible with the activation of migration, vasculogenesis, cellular homeostasis and metabolism of amino acids and reduced apoptosis. These biological activities are possibly regulated by ITGB3 and TGFB1/2 followed by SMAD3, STAT3 and BAG3 activation. In conclusion, this study sheds light on the crosstalk between PDAC cells and associated fibroblasts. Data are available via ProteomeXchange with identifier PXD030974.


Short-term serum deprivation confers sensitivity to taxanes in platinum-resistant human ovarian cancer cells.
Based on the evidences showing that serum deprivation provokes apoptosis in a variety of cells, we have investigated the effect of serum deprivation on drug sensitivity. After human ovarian cancer cells were preincubated in 0.5 % serum containing medium for 12 hours, cellular drug sensitivities were determined by colony-forming assay. Serum deprivation treatment resulted in significant increase in paclitaxel sensitivity by factors of mean ± SD, 148.6 ± 28.1 and 10.1 ± 1.0 (n = 3; P < 0.001) fold in platinum-resistant C13 and CP70 cells, respectively. Similarly, serum deprivation induced significant docetaxel sensitivity in these cell lines. However, no enhancement effect of serum deprivation was observed in platinum-sensitive 2008 and A2780 cells. Serum deprivation did not have any effect on the sensitivities to cisplatin, vincristin, and doxorubicin in all of these cells. More than 7-fold increase of apoptotic cells were observed in C13 or CP70 cells when they were treated by serum deprivation followed by paclitaxel compared with the treatment of either serum deprivation or paclitaxel alone. Confocal laser microscopy using rhodamine 123 and flow cytometric analysis with 3,3'-dihexyloxacarbocyanine iodide revealed that serum deprivation decreased mitochondrial membrane potential in C13 or CP70 cells, whereas no change was observed in 2008 and A2780 cells. This indicates that serum deprivation induced depolarization specifically in platinum-resistant cells. Electron microscopy revealed that serum deprivation caused regeneration of mitochondrial matrix structure in C13 or CP70 cells where mitochondria were usually destructed and disappeared. These results indicate that serum deprivation confers taxane hypersensitivity specifically in platinum-resistant cells by recovering their impaired mitochondrial functions. The evidence might be clinically beneficial for the development of new chemotherapeutic technology, particularly for the patients with platinum-resistant ovarian cancer.


How to use … the Monospot and other heterophile antibody tests.
Epstein-Barr virus (EBV) is a highly prevalent virus, transmitted via saliva, which often causes asymptomatic infection in children but frequently results in infectious mononucleosis in adolescents. Heterophile antibody tests, including the Monospot test, are red cell or latex agglutination assays, which detect antired cell antibodies produced as part of a polyclonal antibody response occurring during EBV infection. Heterophile antibody tests are rapid, cheap and specific tests that can be performed from the onset of symptoms of infectious mononucleosis. In adolescents, heterophile antibody tests have high specificity and sensitivity in the diagnosis of primary acute EBV infection. However, the tests have low sensitivity and low negative predictive value in young children and are not useful under the age of 4. Heterophile tests may be positive in other viral infections, autoimmune disease and haematological malignancies, but do not appear to be positive in primary bacterial infection. Virus-specific serology is required in children under the age of 4 or if an older child is heterophile negative. Virus-specific serology allows diagnosis and the pattern of positivity and negativity enables the clinician to stage the EBV infection. Virus-specific serology appears to have better sensitivity in young children, but there is cross-reaction with other herpesvirus infections, a longer turnaround time and it is more expensive to perform. Further research is needed to establish which children benefit from and hence require testing for heterophile antibodies, the cost-effectiveness of EBV investigations and whether heterophile titres have predictive value for the severity of infection and the likelihood of complications.


Human herpesvirus 6A and axonal injury before the clinical onset of multiple sclerosis.
Recent research indicates that multiple sclerosis is preceded by a prodromal phase with elevated levels of serum neurofilament light chain (sNfL), a marker of axonal injury. The effect of environmental risk factors on the extent of axonal injury during this prodrome is unknown. Human herpesvirus 6A (HHV-6A) is associated with an increased risk of developing multiple sclerosis. The objective of this study was to determine if HHV-6A serostatus is associated with the level of sNfL in the multiple sclerosis prodrome, which would support a causative role of HHV-6A. A nested case-control study was performed by crosslinking multiple sclerosis registries with Swedish biobanks. Individuals with biobank samples collected before the clinical onset of multiple sclerosis were included as cases. Controls without multiple sclerosis were randomly selected, matched for biobank, sex, sampling date and age. Serostatus of HHV-6A and Epstein-Barr virus (EBV) was analysed with a bead-based multiplex assay. The concentration of sNfL was analysed with Single molecule array technology. The association between HHV-6A serology and sNfL was assessed by stratified t-tests and linear regressions, adjusted for EBV serostatus and sampling age. Within-pair ratios of HHV-6A seroreactivity and sNfL were calculated for each case and its matched control. To assess the temporal relationship between HHV-6A antibodies and sNfL, these ratios were plotted against the time to the clinical onset of multiple sclerosis and compared using locally estimated scatterplot smoothing regressions with 95% confidence intervals (CI). Samples from 519 matched case-control pairs were included. In cases, seropositivity of HHV-6A was significantly associated with the level of sNfL (+11%, 95% CI 0.2-24%, P = 0.045), and most pronounced in the younger half of the cases (+24%, 95% CI 6-45%, P = 0.007). No such associations were observed among the controls. Increasing seroreactivity against HHV-6A was detectable before the rise of sNfL (significant within-pair ratios from 13.6 years vs 6.6 years before the clinical onset of multiple sclerosis). In this study, we describe the association between HHV-6A antibodies and the degree of axonal injury in the multiple sclerosis prodrome. The findings indicate that elevated HHV-6A antibodies both precede and are associated with a higher degree of axonal injury, supporting the hypothesis that HHV-6A infection may contribute to multiple sclerosis development in a proportion of cases.


Immune Response to Initial and Booster SARS-CoV-2 mRNA Vaccination in Patients Treated with Siponimod-Final Analysis of a Nonrandomized Controlled Clinical Trial (AMA-VACC).
Evidence on SARS-CoV-2 mRNA vaccination under siponimod treatment is rare. AMA-VACC is a prospective, open-label clinical study on SARS-CoV-2 mRNA vaccination during ongoing siponimod treatment (cohort 1), during siponimod interruption (cohort 2), or during treatment with other disease-modifying therapies or without therapy (cohort 3). SARS-CoV-2-specific antibodies and T-cell reactivity were measured six months after the initial vaccination and one month after the booster. 41 patients were recruited into cohort 1 (n = 17), cohort 2 (n = 4), and cohort 3 (n = 20). Seroconversion for SARS-CoV-2 neutralizing antibodies was reached by 50.0%, 100.0%, and 90.0% of patients at month 6 and by 81.3%, 100.0%, and 100.0% one month after booster (cohorts 1, 2, and 3, respectively). Antibody levels in cohort 1 increased after the booster compared to month 6 but remained lower compared to cohorts 2 and 3. T-cell responses were seen in 28.5%, 25.0%, and 73.7% at month 6 and in 28.6%, 50.0%, and 83.3% after the booster (cohorts 1, 2, and 3, respectively). In cohort 1, the extent of T-cell response was lower at month 6 compared to cohorts 2 and 3 but reached almost similar levels after the booster. The antibody and T-cell responses support SARS-CoV-2 (booster) vaccines in siponimod-treated patients.


Pre-Endoscopy real-time PCR testing for SARS-CoV2 does not reduce health care workers infection and is associated with a higher reduction of endoscopic activity in an outpatient setting.
The role of pre-procedure SARS-CoV2 testing in digestive endoscopy is still debated. AGA guidelines recommend against pre-procedure testing considering low prevalence of SARS- CoV2 infection in the general population and low incidence of infection among endoscopy units Health Care Workers (HCWs). However, no studies have compared pre-procedure testing associated to symptom screening vs. symptom screening alone in reducing the risk of infection for HCWs. Main aim of the present study is to compare the risk of infection for HCWs in different Endoscopy Units adopting different pre-endoscopy screening and operating in two nearby hospital of the same region in Northern Italy in pre-vaccination period. For outpatients in the Endoscopy Unit of Trento (Unit 1) only pre-procedure symptom screening was performed, while in the Endoscopy Unit of Bolzano (Unit 2) pre-procedure symptom screening and negative pre-procedure real-time PCR were requested. Secondary aims were to assess the impact of pre-procedure real-time PCR testing on endoscopic activity and diagnostic delay. Retrospective data collection on a prospectively maintained database was performed, including outpatient endoscopy procedures performed between June 1st 2020 and February 28th 2021 in Unit 1 and Unit 2. No differences in terms of infection rate in HCWs have been identified in Unit 1 and Unit 2 (9.0 vs. 19.3% P=0.2) over a nine-month period. Moreover, in the unit performing pre- procedure real-time PCR before endoscopy a significantly higher reduction in endoscopic activity has been recorded (61.9% vs. 53.4%; P<0.01). In patients with positive real-time PCR, endoscopy was performed with a mean delay of 61.7 days (range 9-294) and 22.5% of them were lost at follow-up and did not undergo any endoscopic procedure in the following 12 months. This study supports the AGA recommendation suggesting that pre-endoscopy real-time PCR is an expensive and time-consuming procedure without proven benefits in an outpatient setting.


Cardiovascular risk and renal injury profile in subjects with type 2 diabetes and non-albuminuric diabetic kidney disease.
In the last years, the classical pattern of diabetic kidney disease (DKD) has been partially overcome, because of the uncovering of a new DKD phenotype with significant renal dysfunction without presence of albuminuria: the non-albuminuric DKD (NA-DKD). To date, the cardiovascular risk associated with this phenotype is still debated. We investigated the cardiovascular risk and renal injury profile of NA-DKD subjects in comparison with other DKD phenotypes. Pulse wave velocity (PWV), intima-media thickness, presence of carotid atherosclerotic plaque, renal resistive index (RRI), and a panel of urinary biomarkers of kidney injury were evaluated in 160 subjects with type 2 diabetes, stratified according to estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR) into four groups: controls (UACR < 30 mg/g and eGFR ≥ 60 mL/min/1.73 m2), A-DKD (Albuminuric-DKD, UACR ≥ 30 mg/g and eGFR ≥ 60 mL/min/1.73 m2), NA-DKD (UACR < 30 mg/g and eGFR < 60 mL/min/1.73 m2), AL-DKD (Albuminuric and Low eGFR-DKD; UACR ≥ 30 mg/g and eGFR < 60 mL/min/1.73 m2). Subjects with NA-DKD showed a higher PWV (11.83 ± 3.74 m/s vs. 10.24 ± 2.67 m/s, P = 0.045), RRI (0.76 ± 0.11 vs. 0.71 ± 0.09, P = 0.04), and prevalence of carotid atherosclerotic plaque (59% vs. 31%, P = 0.009) compared with controls. These characteristics were similar to those of subjects with AL-DKD, whereas the profile of A-DKD subjects was closer to controls. After multiple regression analyses, we found that RRI, that is in turn influenced by eGFR (β = - 0.01, P = 0.01), was one of the major determinants of PWV (β = 9.4, P = 0.02). Urinary TreFoil Factor 3, a marker of tubular damage, was higher in NA-DKD subjects vs. controls (1533.14 ± 878.31 ng/mL vs. 1253.84 ± 682.17 ng/mL, P = 0.047). Furthermore, after multiple regression analyses, we found that urinary osteopontin was independently associated with PWV (β = 2.6, P = 0.049) and RRI (β = 0.09, P = 0.006). Our data showed a worse cardiovascular and renal injury profile in NA-DKD subjects. This finding emphasizes the central role of eGFR in the definition of cardiovascular risk profile of diabetic subjects together with albuminuria.


The influence of interimplant distance and attachment type on the retention characteristics of mandibular overdentures on 2 implants: 6-month fatigue retention values.
This in vitro study evaluated the 6-month fatigue retention provided by 5 paired overdenture attachments placed at 3 different interimplant distances (19, 23, and 29 mm). Mean fatigue retention was calculated for each attachment type and compared with the retention produced by the other attachments tested and the initial retention values published earlier. Interimplant distance was found to play a significant role only in the retention of the Hader bar with red and yellow clips. A significant reduction in retention values was observed for 4 of 5 attachment types.


Extracellular Ca2+ Is Required for Fertilization in the African Clawed Frog, Xenopus laevis.
The necessity of extracellular Ca2+ for fertilization and early embryonic development in the African clawed frog, Xenopus laevis, is controversial. Ca2+ entry into X. laevis sperm is reportedly required for the acrosome reaction, yet fertilization and embryonic development have been documented to occur in high concentrations of the Ca2+ chelator BAPTA. Here we sought to resolve this controversy. Using the appearance of cleavage furrows as an indicator of embryonic development, we found that X. laevis eggs inseminated in a solution lacking added divalent cations developed normally. By contrast, eggs inseminated in millimolar concentrations of BAPTA or EGTA failed to develop. Transferring embryos to varying solutions after sperm addition, we found that extracellular Ca2+ is specifically required for events occurring within the first 30 minutes after sperm addition, but not after. We found that the fluorescently stained sperm were not able to penetrate the envelope of eggs inseminated in high BAPTA, whereas several had penetrated the vitelline envelope of eggs inseminated without a Ca2+ chelator, or with BAPTA and saturating CaCl2. Together these results indicate that fertilization does not occur in high concentrations of Ca2+ chelators. Finally, we found that the jelly coat includes >5 mM of readily diffusible Ca2+. Taken together, these data are consistent with requirement of extracellular Ca2+ for fertilization. Based on our findings, we hypothesize that the jelly coat surrounding the egg acts as a reserve of readily available Ca2+ ions to foster fertilization in changing extracellular milieu.


Risk of Necrotizing Enterocolitis Associated With the Single Nucleotide Polymorphisms VEGF C-2578A, IL-18 C-607A, and IL-4 Receptor α-Chain A-1902G: A Validation Study in a Prospective Multicenter Cohort.
The etiology of necrotizing enterocolitis (NEC) is multifactorial and an underlying genetic predisposition to NEC is increasingly being recognized. A growing number of studies identified single nucleotide polymorphisms (SNPs) of selected genes with potential biological relevance in the development of NEC. However, few of these genetic studies have been replicated in validation cohorts. We aimed to confirm in a cohort of 358 preterm newborns (gestational age <30 weeks, 26 cases of NEC ≥ Bell stage II) the association with NEC of three candidate SNPs: the vascular endothelium growth factor (VEGF) C-2578A polymorphism (rs699947), the interleukin (IL)-18 C-607A polymorphism (rs1946518), and the IL-4 receptor α-chain (IL-4Rα) A-1902G polymorphism (rs1801275). We observed that allele and genotype frequencies of the three SNPs did not significantly differ between the infants with and without NEC. In contrast, the minor G-allele of the IL-4Rα A-1902G polymorphism was significantly less frequent in the group of 51 infants with the combined outcome NEC or death before 34 weeks postmenstrual age than in the infants without the outcome (0.206 vs. 0.331, P = 0.01). In addition, a significant negative association of the G-allele with the combined outcome NEC or death was found using the dominant (adjusted odds ratio, aOR: 0.44, 95% CI 0.21-0.92), recessive (aOR 0.15, 95% CI 0.03-0.74), and additive (aOR 0.46, 95% CI 0.26-0.80) genetic models. In conclusion our study provides further evidence that a genetic variant of the IL-4Rα gene may contribute to NEC.


Bremsstrahlung production by potassium-40 in muscle.
The bremsstrahlung spectrum produced when 1320 keV beta particles, emitted by the naturally occurring isotope 40K, are absorbed in muscle has been calculated. With reference to the external measurement of 239Pu in the lung using the 17 keV U L x-rays, a simple model was used to estimate the number of bremsstrahlung photons with energies between 12 and 25 keV that would emerge from the chest wall of a normal subject. This was calculated to be 3 min-1 for a detection area of 628 cm2, although internal bremsstrahlung may increase this to 4 min-1. The latter figure is a factor of approximately three lower than the counting rate observed when a pair of phoswich NaI detectors of the same total area are placed over an average subject. Possible reasons for this discrepancy are discussed.


Neoadjuvant chemoradiotherapy with 5-fluorouracil by bolus.
Neoadjuvant chemoradiotherapy (CT-RT) with continuous infusion (c.i.) 5-fluorouracil (5-FU) before resection of high-risk rectal cancer improves overall survival (OS) and pelvic control. Since the presence of cardiomiopathy may contraindicate c.i. of 5-FU, an alternative regimen of 5-FU CT-RT was prospectively studied in these patients. From October 2000 to December 2006, patients with clinical stage T3 or T4, or node-positive disease were assigned according to their cardiological status to receive weekly 5-FU bolus administration during radiotherapy (RT). The preoperative treatment consisted of 5,040 cGy, delivered infractions of 180 cGy per day, five days per week, and 5-FU, given in 15 minutes at a dose of 450 mg/m2 of body surface area weekly during all radiotherapy. Surgery was performed six weeks after the completion of CT-RT. The primary endpoint was disease-free survival (DFS). Fifty-one patients received preoperative CH-RT. The 2-year OS rate was 92.3% and the 3-year DFS was 87.5%. The five-year cumulative incidence of local relapse was 3.9%. Grade 3 acute toxic effects occurred in 19.6% of the patients; worsening of patient's cardiopathy was never reported. Patients with cardiopathy developed similar local control and DFS, toxicity and OS with 5-FU administered weekly by bolus as those reported by literature data.


How organizational research can avoid the pitfalls of a co-optation perspective: analyzing gender equality work in Austrian universities with organizational institutionalism.
The concept of co-optation offers vocabulary to discuss how concerns and demands of feminist movements are transformed on their way to, and within, mainstream organizations and policymaking. However, applications of this concept can have problematic implications, failing to grasp the complexity of social change efforts and contributing to divisions, rather than alliances, between different groups that work and fight for gender equality. This article argues that conceptual tools from organizational institutionalism can help to avoid these pitfalls by capturing the ambivalence of organizational change initiatives, and allowing us to identify not only counterintentional effects, but also subtle and unexpected opportunities of organizational gender equality work. I illustrate my arguments with empirical examples from research on gender equality work in Austrian universities.


Evaluating symptoms to improve quality of life in patients with chronic stable angina.
Chronic stable angina (CSA) is a significant problem in the United States that can negatively impact patient quality of life (QoL). An accurate assessment of the severity of a patient's angina, the impact on their functional status, and their risk of cardiovascular complications is key to successful treatment of CSA. Active communication between the patient and their healthcare provider is necessary to ensure that patients receive optimal therapy. Healthcare providers should be aware of atypical symptoms of CSA in their patients, as patients may continue to suffer from angina despite the availability of multiple therapies. Patient questionnaires and symptom checklists can help patients communicate proactively with their healthcare providers. This paper discusses the prevalence of CSA, its impact on QoL, and the tools that healthcare providers can use to assess the severity of their patients' angina and the impact on QoL.


Phenolic indeno[1,2-b]indoles as ABCG2-selective potent and non-toxic inhibitors stimulating basal ATPase activity.
Ketonic indeno[1,2-b]indole-9,10-dione derivatives, initially designed as human casein kinase II (CK2) inhibitors, were recently shown to be converted into efficient inhibitors of drug efflux by the breast cancer resistance protein ABCG2 upon suited substitutions including a N (5)-phenethyl on C-ring and hydrophobic groups on D-ring. A series of ten phenolic and seven p-quinonic derivatives were synthesized and screened for inhibition of both CK2 and ABCG2 activities. The best phenolic inhibitors were about threefold more potent against ABCG2 than the corresponding ketonic derivatives, and showed low cytotoxicity. They were selective for ABCG2 over both P-glycoprotein and MRP1 (multidrug resistance protein 1), whereas the ketonic derivatives also interacted with MRP1, and they additionally displayed a lower interaction with CK2. Quite interestingly, they strongly stimulated ABCG2 ATPase activity, in contrast to ketonic derivatives, suggesting distinct binding sites. In contrast, the p-quinonic indenoindoles were cytotoxic and poor ABCG2 inhibitors, whereas a partial inhibition recovery could be reached upon hydrophobic substitutions on D-ring, similarly to the ketonic derivatives.


Sudden massive neck swelling due to hemorrhage of a thyroid adenoma: a case report.
Sudden swelling of the neck is an emergency situation that can be life-threatening for the patient. Therefore, an understanding of the possible underlying pathology is of great importance. Sudden massive swelling of the neck because of intralesional bleeding of a thyroid adenoma is seldom encountered but must be considered. Such massive swelling caused by spontaneous bleeding of a thyroid adenoma has not yet been described in the literature. We report the case of a 71-year-old Caucasian man with sudden massive neck swelling due to intralesional bleeding of a thyroid adenoma. We present his clinical history, physical examination results, computed tomography (CT) scans, and histological findings after surgery. He presented with sudden massive swelling of the left side of his neck after sneezing while working with his hands over his head. An ear, nose, and throat examination showed a painless swelling of the left side of his neck and a displacement of his larynx to the right. CT scans revealed a mass originating from the left lobe of his thyroid gland and the mass displaced his larynx and trachea. A surgical exploration showed a greatly enlarged left lobe of his thyroid gland. A histopathological examination showed a hemorrhagic infarction of a follicular thyroid adenoma. Sudden intralesional bleeding of a thyroid adenoma is a rare condition but one that should be considered in cases of sudden and massive swelling of the neck.


The p53 inhibitor pifithrin-alpha is a potent agonist of the aryl hydrocarbon receptor.
The tumor suppressor protein p53 is currently a target of emerging drug therapies directed toward neurodegenerative diseases, such as Alzheimer's and Parkinson's, and side effects associated with cancer treatments. Of this group of drugs, the best characterized is pifithrin-alpha, a small molecule that inhibits p53-dependent apoptosis through an undetermined mechanism. In this study, we have used a number of molecular approaches to test the hypothesis that pifithrin-alpha acts as an aryl hydrocarbon receptor (AhR) agonist and, in this manner, inhibits the actions of p53. Toward this end, we have found that pifithrin-alpha is a potent AhR agonist as determined by its ability to bind the AhR, induce formation of its DNA binding complex, activate reporter activity, and up-regulate the classic AhR target gene CYP1A1. However, examination of its ability to inhibit p53-mediated gene activation and apoptosis revealed that these actions occurred via an AhR-independent manner. The significance of this study is based on the fact that activation of the AhR is typically associated with an increase in phase I and phase II metabolizing enzymes and adverse biological events such as tumor promotion that may contribute to untoward effects of pifithrin-alpha. Hence, this work will aid in the future design of more specific members of this important class of p53 inhibitors for use in a clinical setting.


Behavioral evidence for a role of alpha-gustducin in glutamate taste.
The taste perception of monosodium glutamate (MSG) is termed 'umami'. Two putative taste receptors for glutamate have been identified, a truncated form of mGluR4 (taste-mGluR4) and the presumed heterodimer T1R1 + T1R3. Both receptors respond to glutamate when expressed in heterologous cells, but the G protein involved is not known. Galpha-Gustducin mediates the transduction of several bitter and sweet compounds; however, its role in umami has not been determined. We used standard two-bottle preference tests on alpha-gustducin knockout (KO) and wildtype (WT) mice to compare preferences for ascending concentrations of MSG and MSG + 5'-inosine monophosphate (IMP). A Latin Square was used to assign the order of tastants presented to each mouse. Statistical comparisons between KO and WT mice revealed that whereas WT mice preferred solutions of MSG and MSG + IMP over water, KO mice showed little preference for these stimuli. Denatonium and sucrose served as control stimuli and, as shown previously, WT mice prefered sucrose and avoided denatonium significantly more than did KO mice. Naïve mice were also tested, and while prior exposure to taste stimuli influenced the magnitude of the preferences, experience did not change the overall pattern of intake. These data suggest that alpha-gustducin plays a role in glutamate taste.


The Ob protein (leptin) and the kidney.
Mutation of the Ob gene, which encodes for leptin, or mutation of the leptin receptor leads to obesity in mice. Humans, for the most part, have a positive correlation of leptin with body fat mass suggesting possible defects in leptin effector mechanisms that may contribute to obesity. As patients on hemodialysis have difficulty with appetite, we investigated whether leptin is cleared by the kidney and is elevated in hemodialysis patients. In patients with intact renal function there was a net renal uptake of 12% of circulating leptin, whereas in patients with renal insufficiency there was no renal uptake of leptin. In a separate cohort of 36 patients with end-stage renal disease (ESRD), peripheral leptin levels factored for body mass index was increased by fourfold as compared to a group of healthy controls (N = 338). The leptin receptor exists in a long and short form, with the long form primarily expressed in the hypothalamus but also in the lungs and kidneys of the mouse. Further studies are necessary to clarify the role of leptin in regulating appetite in patients with ESRD and the role of leptin in directly affecting kidney function via its receptors.


Direct Electrochemical Determination of Peroxide-Type Explosives Using Well-Dispersed Multi-Walled Carbon Nanotubes/Polyethyleneimine-Modified Glassy Carbon Electrodes.
The sensitive and selective determination of peroxide-based explosives (PBEs) in the field/on site is an important analytical challenge. Most methods claiming to detect PBEs are indirect, actually detecting their decomposition product, H2O2. Here, we present an electrochemical sensor for direct detection of organic peroxide explosives, that is, triacetone triperoxide (TATP) and hexamethylenetriperoxide diamine (HMTD), using well-dispersed multiwalled carbon nanotubes/polyethyleneimine (MWCNTs/PEI)-modified glassy carbon (GC) electrode, namely, GC/MWCNTs/PEI electrode. This is the first use of the conductive polyelectrolyte PEI as an electrode modifier for pristine PBE sensing. The potential range, scan rate, solvent selection, and supporting electrolyte concentration were optimized for PBEs. As a distinct advantage over other similar methods, our sensor electrode responded to intact TATP solutions in neutral medium, meaning that TATP did not interact with acids/bases that would transform it into H2O2. Calibration curves were linear in the range of 10-200 mg L-1 for TATP and 25-200 mg L-1 for HMTD. Using differential pulse voltammetry, detection limits of 1.5 mg L-1 TATP and 3.0 mg L-1 HMTD were obtained from direct electrochemical reduction in 80/20% (v/v) H2O-acetone solvent medium. Electroactive camouflage materials such as passenger belongings (e.g., sweetener, detergent, sugar, and paracetamol-caffeine-based analgesic drugs), common ions, and other explosives were shown not to interfere with the proposed method. The nonresponsive behavior of our electrode to H2O2 prevents "false positives" from other peroxide materials of everyday use. This electrochemical sensor could also detect other nitro-explosives at different potentials and was statistically validated against standard GC-MS and spectrophotometric methods.


Rice BiP3 regulates immunity mediated by the PRRs XA3 and XA21 but not immunity mediated by the NB-LRR protein, Pi5.
Plant innate immunity is mediated by pattern recognition receptors (PRRs) and intracellular NB-LRR (nucleotide-binding domain and leucine-rich repeat) proteins. Overexpression of the endoplasmic reticulum (ER) chaperone, luminal-binding protein 3 (BiP3) compromises resistance to Xanthomonas oryzae pv. oryzae (Xoo) mediated by the rice PRR XA21 [12]. Here we show that BiP3 overexpression also compromises resistance mediated by rice XA3, a PRR that provides broad-spectrum resistance to Xoo. In contrast, BiP3 overexpression has no effect on resistance mediated by rice Pi5, an NB-LRR protein that confers resistance to the fungal pathogen Magnaporthe oryzae (M. oryzae). Our results suggest that rice BiP3 regulates membrane-resident PRR-mediated immunity.


Effects of Homeopathic Preparations of Mercurius corrosivus on the Growth Rate of Moderately Mercury-Stressed Duckweed Lemna gibba L.
A bioassay with severely mercury-stressed duckweed (Lemna gibba L.) had revealed growth-inhibiting effects of homeopathically potentised mercury(II) chloride (Mercurius corrosivus, Merc-c.). We hypothesised that effects of potentised preparations are dependent on the stress level of the organisms used in the bioassay. The aim of the present investigation was to examine the response of duckweed to potentised Merc-c. at a lower stress level. Duckweed was moderately stressed with 2.5 mg/L mercury(II) chloride for 48 hours. Afterwards plants grew in either Merc-c. (seven different potency levels, 24x-30x) or water controls (unsuccussed or succussed water) for 7 days. Growth rates of the frond (leaf) area were determined using a computerised image-analysis system for day 0-3 and 3-7. Three independent experiments with potentised Merc-c. and three systematic negative control experiments were performed. All experiments were randomised and blinded. Unsuccussed and succussed water did not significantly differ in their effects on duckweed growth rate. The systematic negative control experiments did not yield any significant effects, thus providing evidence for the stability of the experimental system. Data from the two control groups and the seven treatment groups (Merc-c. 24x-30x) were each pooled to increase statistical power. Duckweed growth rates for day 3-7 were enhanced (p < 0.05) after application of Merc-c. compared with the controls. Growth rates for day 0-3 were not influenced by the homeopathic preparations. Moderately mercury-stressed Lemna gibba L. yielded evidence of growth-enhancing specific effects of Merc-c. 24x-30x in the second observation period (day 3-7). This observation is complementary to previous experiments with severely mercury-stressed duckweed, in which a decrease in growth was observed in the first observation period (day 0-3). We hypothesise that the differing results are associated with the level of stress intensity (moderate vs. severe).


Aspirin inhibits camptothecin-induced p21CIP1 levels and potentiates apoptosis in human breast cancer cells.
The ability of aspirin to trigger apoptosis in cancer cells is well known and is consistent with the clinical and epidemiological evidence on its chemopreventive effects in curtailing epithelial cancers, including breast cancer. We hypothesized that the anticancer effects of aspirin may involve acetylation of the tumor suppressor protein p53, a known regulator of apoptosis. In the present study, we determined if aspirin at the physiologically achievable concentration of 100 microM acetylates p53 and modulates the expression of p21CIP1, a protein involved in cell cycle arrest, and Bax, a pro-apoptotic protein. Using MDA-MB-231 human breast cancer cells, we demonstrate that aspirin at 100 microM concentration markedly acetylated the p53 protein, which was primarily localized to the nucleus. Aspirin induced p21CIP1 protein levels in a transient fashion in contrast to the sustained induction of Bax. The induction of p21CIP1 protein levels began at 3 h and was maximal at 6-8 h; however, it decreased to control levels by 30 h. In contrast, the anticancer drug, camptothecin (CPT) induced a steady accumulation of p21CIP1 protein. Remarkably, when cells were co-treated with aspirin and CPT, p21CIP1 levels were drastically downregulated, and this phenomenon was observed in many cancer cell lines. Incubation of recombinant p21 with cytoplasmic extracts from aspirin-treated cells caused its degradation suggesting the involvement of proteases in the disappearance of p21CIP1. Consistent with this data, aspirin decreased the survival of CPT-treated cells and greatly increased the extent of apoptosis. Our observation that aspirin has the ability to inhibit p21CIP1 after its initial induction has important implications in chemotherapy, and suggests its potential use to increase the efficacy of anticancer agents.


Aging and atrial fibrillation: A vicious circle.
Atrial fibrillation (AF) is the commonest sustained cardiac arrhythmia observed in clinical practice. Its prevalence increases dramatically with advancing age. This review article discusses the recent advances in studies investigating the relationship between aging and AF and the possible underlying mechanisms.


Divergent gene regulation and growth effects by NF-kappa B in epithelial and mesenchymal cells of human skin.
NF-kappa B regulates normal and pathological processes, including neoplasia, in a tissue-context-dependent manner. In skin, NF-kappa B is implicated in epidermal homeostasis as well as in the pathogenesis of squamous cell carcinoma; however, its function in the underlying mesenchymal dermis has been unclear. To gain insight into NF-kappa B roles in these two adjacent cutaneous tissue compartments, NF-kappa B effects on expression of 12 435 genes were determined in epidermal keratinocytes and dermal fibroblasts. Although NF-kappa B induced proinflammatory and antiapoptotic genes in both settings, it exhibited divergent effects on growth regulatory genes. In keratinocytes, but not in fibroblasts, NF-kappa B induced p21(CIP1), which was sufficient to inhibit growth of both cell types. Levels of growth inhibitory factor (GIF), in contrast, were increased by NF-kappa B in both settings but inhibited growth only in keratinocytes. These findings indicate that transcription factors such as NF-kappa B can program tissue-selective effects via both differential target gene induction as well as by inducing common targets that exert differing effects depending on cellular lineage.


Visual receptive field properties of neurons in the superficial superior colliculus of the mouse.
The mouse is a promising model in the study of visual system function and development because of available genetic tools. However, a quantitative analysis of visual receptive field properties had not been performed in the mouse superior colliculus (SC) despite its importance in mouse vision and its usefulness in developmental studies. We have made single-unit extracellular recordings from superficial layers of the SC in urethane-anesthetized C57BL/6 mice. We first map receptive fields with flashing spot stimuli and show that most SC neurons have spatially overlapped ON and OFF subfields. With drifting sinusoidal gratings, we then determine the tuning properties of individual SC neurons, including selectivity for stimulus direction and orientation, spatial frequency tuning, temporal frequency tuning, response linearity, and size preference. A wide range of receptive field sizes and selectivity are observed across the population and in various subtypes of SC neurons identified morphologically. In particular, orientation-selective responses are discovered in the mouse SC, and they are not affected by cortical lesion or long-term visual deprivation. However, ON/OFF characteristics and spatial frequency tuning of SC neurons are influenced by cortical inputs and require visual experience during development. Together, our results provide essential information for future investigations on the functional development of the superior colliculus.


Long-term low dose dietary resveratrol supplement reduces cardiovascular structural and functional deterioration in chronic heart failure in rats.
A short-term exposure to resveratrol at high dosages exerts a remarkable cardioprotective effect. Whether a long-term exposure to resveratrol at low dosages that can be obtained through consumption of a resveratrol-rich diet is beneficial to heart diseases is unknown. We tested the effects of a resveratrol-enriched diet on cardiovascular remodeling of chronic heart failure (CHF) in rats resulting from permanent ligation of left coronary artery. Two weeks after surgery, rats were started on either a resveratrol-enriched (R; 5 mg/kg per day; n = 23) or normal (Control; n = 23) diet for next 10 months. Serial echocardiography in Control showed a significant decline in LV ejection fraction, increases in LV end-systolic and end-diastolic volumes, and expansion in myocardial infarct from pre-treatment values. In R, compared with Control, there were substantial improvements in those parameters. End-point LV pressure-volume loop analysis showed a significantly improved LV systolic function and AV-coupling, an index of energy transfer efficacy between the heart and aortic tree, in R compared with Control (p < 0.05). Aortic pulse wave velocity, a measure of arterial stiffness, was significantly lower in R (389 ± 15 cm/s; p < 0.05) compared with Control (489 ± 38 cm/s). These results demonstrated that long-term dietary resveratrol supplement reduces cardiovascular structural and functional deterioration in CHF.


Cell surface lactate receptor GPR81 is crucial for cancer cell survival.
The mechanisms that allow cancer cells to adapt to the typical tumor microenvironment of low oxygen and glucose and high lactate are not well understood. GPR81 is a lactate receptor recently identified in adipose and muscle cells that has not been investigated in cancer. In the current study, we examined GPR81 expression and function in cancer cells. We found that GPR81 was present in colon, breast, lung, hepatocellular, salivary gland, cervical, and pancreatic carcinoma cell lines. Examination of tumors resected from patients with pancreatic cancer indicated that 94% (148 of 158) expressed high levels of GPR81. Functionally, we observed that the reduction of GPR81 levels using shRNA-mediated silencing had little effect on pancreatic cancer cells cultured in high glucose, but led to the rapid death of cancer cells cultured in conditions of low glucose supplemented with lactate. We also observed that lactate addition to culture media induced the expression of genes involved in lactate metabolism, including monocarboxylase transporters in control, but not in GPR81-silenced cells. In vivo, GPR81 expression levels correlated with the rate of pancreatic cancer tumor growth and metastasis. Cells in which GPR81 was silenced showed a dramatic decrease in growth and metastasis. Implantation of cancer cells in vivo was also observed to lead to greatly elevated levels of GPR81. These data support that GPR81 is important for cancer cell regulation of lactate transport mechanisms. Furthermore, lactate transport is important for the survival of cancer cells in the tumor microenvironment. Cancer Res; 74(18); 5301-10. ©2014 AACR.


Understanding the preferences for different types of urban greywater uses and the impact of qualitative attributes.
Greywater reuse can allow substantial improvements in the efficiency of potable water systems. However, widespread uptake of greywater reuse depends on its acceptability by the population. Previous studies have assessed the implementation costs of greywater reuse technology, and considered its acceptability in principle. Although cost is clearly very important in terms of adopting/installing the technology, the actual perception of greywater reuse is crucial in driving the acceptability of use and the long-term success of the technology. This study uses discrete choice models to quantify, for the first time, the preferences of different socio-economic groups for greywater of different quality (colour, odour) and for different uses inside homes. A stated choice survey that removed the influence of installation costs was developed, and implemented in Santiago, Chile. Although legislation allows greywater use in Santiago, it does not take place at any meaningful scale. Results show that, in decreasing order of preference, there is an overall acceptance for using high quality treated greywater for toilet flushing, laundry, garden irrigation, hand washing and, shower/bathtub use, but not for drinking. When the quality of appearance in terms of colour and odour gets worse, monetary incentives could be needed even for those uses that do not involve human contact. Gender, age, educational level, water expenditure level, and in particular previous knowledge about greywater reuse, are important determinants of acceptability and thus willingness to pay for greywater use; however, their importance varies according to the type of use. Our results provide important insights for understanding the conditions that would precipitate rapid and wide uptake of greywater reuse in cities, and thereby make better use of limited water resources.


Secondary rhinoplasty in nasal deformity associated with the unilateral cleft lip.
The secondary nasal deformity of the unilateral cleft lip involves a retrodisplaced dome of the ipsilateral nasal tip, hooding of the alar rim, a secondary alar-columellar web, and other deficiencies. The sliding-flap cheilorhinoplasty effectively corrects these deformities using a laterally based chondrocutaneous flap. We modified this technique by using an open rhinoplasty approach with the laterally based chondrocutaneous sliding flap. Columellar struts and shield grafts were some of the techniques combined with this approach to produce optimal results. In a total of 7 patients, we performed both the original sliding-flap cheilorhinoplasty and the modified open rhinoplasty, which are described and discussed herein. The laterally based sliding-flap cheilorhinoplasty is an effective technique for correcting both the secondary nasal deformity and the lip scar associated with the unilateral cleft lip.


Isolated noncompaction of the left ventricular myocardium in adults: a systematic overview.
Owing to inconsistent diagnostic criteria and small heterogeneous cohorts, little is known about the long-term outcomes of adult left ventricular noncompaction (LVNC), a rare cardiomyopathy with potentially serious outcomes. This systematic overview aimed to better delineate the natural history of adult LVNC. A comprehensive computerized search using "noncompaction" and its synonyms initially identified 206 articles, with reference lists subsequently hand scanned. These searches yielded 5 studies that were eligible for this systematic overview, identifying adult cohorts with isolated LVNC diagnosed by similar echocardiographic criteria. This combined cohort (n = 241) was followed for a mean duration of 39 months. The annualized event rate was 4% for cardiovascular deaths, 6.2% for cardiovascular death and its surrogates (heart transplantation and appropriate implantable cardioverter-defibrillator shocks), and 8.6% for all cardiovascular events (death, stroke, implantable cardioverter-defibrillator shocks, and heart transplantation.) Familial occurrence of LVNC in first-degree relatives was identified by echocardiography in 30% of index cases who were screened. LVNC is an increasingly recognized cardiomyopathy diagnosed by echocardiography and is associated with familial tendencies, arrhythmias, thromboembolism, advanced heart failure, and death.


Blood product ratio in acute traumatic coagulopathy--effect on mortality in a Scandinavian level 1 trauma centre.
Trauma is the leading cause of loss of life expectancy worldwide. In the most seriously injured patients, coagulopathy is often present on admission. Therefore, transfusion strategies to increase the ratio of plasma (FFP) and platelets (PLT) to red blood cells (RBC), simulating whole blood, have been introduced. Several studies report that higher ratios improve survival in massively bleeding patients. Here, the aim was to investigate the potential effect of increased FFP and PLT to RBC on mortality in trauma patients. In a retrospective before and after study, all trauma patients primarily admitted to a level-one Trauma Centre, receiving blood transfusion, in 2001-3 (n = 97) and 2005-7 (n = 156), were included. In 2001-3, FFP and PLT were administered in accordance with the American Society of Anesthesiologists (ASA) guidelines whereas in 2005-7, Hemostatic Control Resuscitation (HCR) entailing pre-emptive use of FFP and PLT in transfusion packages during uncontrolled haemorrhage and thereafter guided by thrombelastograph (TEG) analysis was employed. The effect of transfusion therapy and coagulopathy on mortality was investigated. Patients included in the early and late period had comparable demography, injury severity score (ISS), admission hematology and coagulopathy (27% vs. 34% had APTT above normal). There was a significant change in blood transfusion practice with shorter time interval from admission to first transfusion (median time 3 min vs.28 min in massive bleeders, p < 0.001), transfusion of higher ratios of FFP:RBC, PLT:RBC and PLT:FFP in the HCR group but 30-day mortality remained comparable in the two periods. In the 2005-7 period, higher age, ISS and Activated Partial Thromboplastin Time (APTT) above normal were independent predictors of mortality whereas no association was fund between blood product ratios and mortality. Aggressive administration of FFP and PLT did not influence mortality in the present trauma population.


Outcomes in thread lift for face, neck, and nose; A prospective chart review study with APTOS.
To evaluate the surgical efficacy and outcomes related to midface, mandible, neck (and double chin), and nose lifting with APTOS thread lift. In this prospective review chart study, a total of 58 patients were included (from July 2018 to July 2019). All participants underwent facial thread lifting using APTOS. The patients were followed up first week, third, and sixth month after lifting surgery. Outcomes were assessed by two surgeons and patients based on the GAIS score. All data were analyzed by SPSS-17 software with chi-square test. A total of 58 patients (Mean ± SD: 52.52 ± 10.58) (F: 45, Mean ± SD:53.13 ± 11.27 years, M:13, Mean ± SD: 50.38 ± 9.43 years) were included in the study. The most common sites for the face-lifting surgery were midface and mandibular (N = 45, 77.5%), neck (N = 10, 17.3%), and nose (N = 3, 5.2%), respectively. The level of satisfaction remained unchanged (after 6 months), about 80%, for the patients, increased from 90.7% (first week) to 94.8% (sixth month) after surgery, and increased from 93.1% (first week) to 94.8% (sixth month after surgery). The highest rate of potential complications after the surgery was related to ecchymosis (17 cases, 30%), followed by complications of pain (N = 10, 17.2%), tumefaction (N = 4, 6.9%), and dimple (N = 1, 1.7%) were reported. The results showed that satisfaction in patients and surgeons increased over time (after 6 months). Postoperative (minor) complications were also assessed and ecchymosis was found to be the most common complication. However, the proportion of postoperative complications was relatively low.


Solid Organ Transplant-Transmitted Tuberculosis Linked to a Community Outbreak - California, 2015.
In the spring of 2015, a local health department (LHD) in county A notified the California Department of Public Health (CDPH) about three adults with close ties to one another and a congregate community site who had received diagnoses of tuberculosis (TB) disease within a 3-month period. Subsequent review revealed matching TB genotypes indicating that the cases were likely part of a chain of TB transmission. Only three TB cases in California in the preceding 2 years shared this same genotype. One of those three previous cases occurred in a lung-transplant recipient who had no identified epidemiologic links to the outbreak. CDPH, multiple LHDs, and CDC conducted an investigation and determined that the lung-transplant donor (patient 1) was epidemiologically linked to the three outbreak cases and had a tuberculin skin test (TST) conversion detected in 2012 upon reentry at a local jail. Three other solid organ recipients from this donor were identified; none had developed TB disease. This investigation suggests that review of organ donors' medical records from high-risk environments, such as jails, might reveal additional information about TB risk. The evaluation of TB in organ recipients could include genotyping analysis (1) and coordination among local, state, and national partners to evaluate the potential for donor-derived TB.


Combination of oral antidiabetic agents with basal insulin versus premixed insulin alone in randomized elderly patients with type 2 diabetes mellitus.
To compare initiation of insulin therapy by adding once-daily insulin glargine to oral antidiabetic agents (OADs) with switching patients to premixed 30% regular, 70% human neutral protamine hagedorn insulin (70/30) without OADs. A 24-week, multicenter, open, randomized (1:1), parallel study. Three hundred sixty-four poorly controlled patients with type 2 diabetes mellitus were treated with once-daily morning insulin glargine with continued OADs (glimepiride+metformin) (glargine+OAD) or twice-daily 70/30 alone. Insulin dosage in each group was titrated to target fasting blood glucose (FBG) of 100 mg/dL or less (<or=5.6 mmol/L) using a weekly titration algorithm. This planned subgroup analysis of the original study was based on 130 insulin-naive patients aged 65 and older with FBG of 120 mg/dL or greater (>or=6.7 mmol/L) and hemoglobin (Hb)A(1c) levels between 7.5% and 10.5% on OADs (glargine+OAD, n=67; 70/30, n=63). HbA(1c), FBG, hypoglycemia, insulin dose, and adverse events were recorded. HbA(1c) decreased from baseline to endpoint for both glargine+OAD (from 8.8% to 7.0%) and 70/30 (from 8.9% to 7.4%); adjusted mean HbA(1c) decrease for glargine+OAD and 70/30 was -1.9% and -1.4%, respectively (P=.003). More patients reached HbA(1c) of 7.0% or less without confirmed nocturnal hypoglycemia with glargine+OAD (n=37, 55.2%) than with 70/30 (n=19, 30.2%) (P=.006). FBG decreased significantly more with glargine+OAD (-57 mg/dL (-3.2 mmol/L)) than with 70/30 (-40 mg/dL (-2.2 mmol/L)) (P=.002). Patients treated with glargine+OAD experienced fewer episodes of any hypoglycemia (3.68/patient-year) than did those treated with 70/30 (9.09/patient-year) (P=.008). In elderly patients, addition of once-daily morning glargine+OAD is a simple regimen to initiate insulin therapy, restoring glycemic control more effectively and with less hypoglycemia than twice-daily 70/30 alone.


Prediction of human femoral bone strength using ultrasound velocity and BMD: an in vitro study.
The stiffness and strength of cancellous bone are important in the management of skeletal diseases such as osteoporosis. These properties are a function not only of bone density but also of bone architecture, some measure of which can be provided by quantitative ultrasound. The ability of quantitative ultrasound and bone mineral density (BMD) to predict stiffness and strength of human femoral heads removed from live subjects during hip replacement was assessed. Stiffness and strength were measured using a uniaxial compression test. Ultrasound velocity was measured using the pulse-submersion technique (McCue CUBAResearch) and BMD using DXA (Lunar DPX-L). Ultrasound velocity (quantitative ultrasound) and stiffness varied with the three orthogonal directions, the highest significance being between the proximo-distal (PD) and antero-posterior (AP) directions (p < 0.0001 for stiffness and p = 0.0003 for velocity). Ultrasound velocity was significantly correlated with compressive bone strength (r = 0.76, p < 0.0001) and stiffness (r = 0.79-0.83, p < 0.0001). BMD was also significantly correlated with compressive strength (r = 0.82, p < 0.0001) and stiffness (r = 0.66-0.81. p < 0.001). Using multiple regression analysis both BMD and velocity were significant predictors of strength (r = 0.88, p = 0.0004 and 0.0054 respectively) and stiffness (r = 0.92, p = 0.0001 and 0.0003 respectively). BMD and velocity were still independent significant predictors of both stiffness (r = 0.93, p < 0.0001 and 0.0001 respectively) and strength (r = 0.89, p < 0.0001 and 0.02) when they were combined as a product (BMDn*Vm). This suggests that BMD measured using DXA, if used in conjunction with ultrasound velocity, may be able to improve osteoporosis risk assessment. The information about femur anisotropy may also be important for hip prosthesis and in vivo modelling.